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Biomedical subjects

M Chu

Publications and source records attributed to M Chu.

At least 19 recordsLinked to original sources
PubMed2001

Fine mapping of Hyplip1 and the human homolog, a potential locus for FCHL.

Familial combined hyperlipidemia (FCHL) is a common genetic dyslipidemia predisposing to premature coronary heart disease (CHD). We previously identified a locus for FCHL on human Chromosome (Chr) 1q21-q23 in 31 Finnish FCHL families. We also mapped a gene for combined hyperlipidemia (Hyplip1) to a potentially orthologous region of mouse Chr 3 in the HcB-19/Dem mouse model of FCHL. The human FCHL locus was, however, originally mapped about 5 Mb telomeric to the synteny border, the centromeric part of which is homologous to mouse Chr 3 and the telomeric part to mouse Chr 1. To further localize the human Hyplip1 homolog and estimate its distance from the peak linkage markers, we fine-mapped the Hyplip1 locus and defined the borders of the region of conserved synteny between human and mouse. This involved establishing a physical map of a bacterial artificial chromosome (BAC) contig across the Hyplip1 locus and hybridizing a set of BACs to both human and mouse chromosomes by fluorescence in situ hybridization (FISH). We narrowed the location of the mouse Hyplip1 gene to a 1.5-cM region that is homologous only with human 1q21 and within approximately 5-10 Mb of the peak marker for linkage to FCHL. FCHL is a complex disorder and this distance may, thus, reflect the well-known problems hampering the mapping of complex disorders. Further studies identifying and sequencing the Hyplip1 gene will show whether the same gene predisposes to hyperlipidemia in human and mouse.

Animals↗
PubMed2001

Human interindividual variability in susceptibility to airborne particles.

Part of the explanation for the persistent epidemiological findings of associations between mortality and morbidity with relatively modest ambient exposures to airborne particles may be that some people are much more susceptible to particle-induced responses than others. This study assembled a database of quantitative observations of interindividual variability in pharmacokinetic and pharmacodynamic parameters likely to affect particle response. The pharmacodynamic responses studied included data drawn from epidemiologic studies of doses of methacholine, flour dust, and other agents that induce acute changes in lung function. In general, the amount of interindividual variability in several of these pharmacodynamic response parameters was greater than the variability in pharmacokinetic (breathing rate, deposition, and clearance) parameters. Quantitatively the results indicated that human interindividual variability of breathing rates and major pharmacokinetic parameters-total deposition and tracheobronchial clearance-were in the region of Log(GSD) = 0.1 to 0.2 (corresponding to geometric standard deviations of 10(.1)-10(.2) or 1.26-1.58). Deposition to the deep lung (alveolar region) appeared to be somewhat more variable: Log(GSD) of about 0.3 (GSD of about 2). Among pharmacodynamic parameters, changes in FEV1 in response to ozone and metabisulfite (an agent that is said to act primarily on neural receptors in the lung) were in the region of Log(GSD) of 0.2 to 0.4. However, similar responses to methacholine, an agent that acts on smooth muscle, seemed to have still more variability (0.4 to somewhat over 1.0, depending on the type of population studied). Similarly high values were suggested for particulate allergens. Central estimates of this kind of variability, and the close correspondence of the data to lognormal distributions, indicate that 99.9th percentile individuals are likely to respond at doses that are 150 to 450-fold less than would be needed in median individuals. It seems plausible that acute responses with this amount of variability could form part of the mechanistic basis for epidemiological observations of enhanced mortality in relation to ambient exposures to fine particles.

Air Pollutants↗
PubMed2001

Susceptibility of the Siberian polecat to subcutaneous and oral Yersinia pestis exposure.

To determine if the Siberian polecat (Mustela eversmannii) represents a suitable model for the study of plague pathogenesis and prevention in the black-footed ferret (Mustela nigripes), polecats were exposed to 10(3), 10(7), or 10(10) Yersinia pestis organisms by subcutaneous injection; an additional group was exposed to Y. pestis via ingestion of a plague-killed mouse. Plague killed 88% of polecats exposed to Y. pestis (71% mortality in the 10(3) group, 100% mortality in the 10(7) and 10(10) groups, and 83% mortality in the mouse-fed group). Within the challenged group, mean day of death post-challenge ranged from 3.6 to 7.6 days; all polecats died on or before day 12 post-challenge. Animals receiving the lowest parenteral dose survived significantly longer than those receiving higher parenteral doses. Within challenged animals, mean survival time was lower in those presenting with significant weight loss by day 3, lethargy, and low fecal output; time to onset of lethargy and other signs was also related to risk of dying and/or plague dose. Six polecats developed serum antibody titers to the Y. pestis F1 protein. Three seropositive polecats survived the initial challenge and a subsequent exposure to a plague-killed mouse, while two seropositive animals later died. This study confirms that the Siberian polecat is susceptible to plague and suggests that this species will offer an appropriate surrogate for black-footed ferrets in future plague studies and related vaccine trials.

Administration, Oral↗
PubMed2001

Excessive weight gain during peritoneal dialysis.

The authors carried out a retrospective chart review in 114 patients treated for at least two years at the Toronto Western Hospital Peritoneal Dialysis Unit and identified eight, who gained an "excessive" amount of weight equal to or greater than 10 kg of their initial weight. These patients had gained an average of 13.1 kg over the preceding two years. They are mostly males and their average age is 51 years. They are well-nourished normotenseive nondiabetics with mostly normal cardiac function. They are adequately dialyzed (per KT/V urea), have little residual renal function and typically have peritoneal membranes characterized by high average transport. According to BIA analysis, this weight gain was likely due to an increase in fat mass accompanied by a trend toward decreasing body-cell mass. This weight gain may be due to increased caloric intake secondary to dialysate glucose absorption in the setting of high average (peritoneal membrane) transport. Such excessive weight gain also may occur if these patients have polymorphism of the UCP-2 gene, which can alter metabolic rate.

Adult↗
PubMed2001

Increased mortality of elderly female peritoneal dialysis patients with diabetes--a descriptive analysis.

Three recent studies using registry data from the United States, in comparing the mortality risks between peritoneal dialysis (PD) and hemodialysis (HD), have consistently found that elderly diabetic women on PD have a higher mortality risk as compared with their counterparts on HD. Though the cause for this observation is not clear, the phenomenon may be unique to the United States. Alternatively, a selection bias impossible to decipher may be at work in these studies, as none of them have data on comorbidity, nutrition, or adequacy of dialysis. Finally, the possibility that elderly diabetic women are, for some reason, more vulnerable to the ill effects of peritoneal dialysis should be considered. We report here a retrospective analysis of 47 diabetic women, above 55 years of age, with end-stage renal disease, who were started on PD and who later died on dialysis. The primary outcome of interest was cause of death. Demographic details about the patients, comorbid conditions, dialysis adequacy, and biochemical parameters at the start of PD were noted. Death in these patients was attributed mainly to vascular causes, and there appeared to be a high prevalence of peripheral vascular disease. Infection was the next major cause of death, being the primary cause in 14 patients. Of these, only 5 patients had peritonitis. On a Cox regression analysis, only patient age and duration of diabetes at onset of dialysis were found to be predictive of vascular death. No factor was found to be predictive of death from infection. It appears that elderly diabetic women on PD die mainly of the long-term complications of diabetes.

Aged↗
PubMed2000

Motional dressed states in a bose-einstein condensate: superfluidity at supersonic speed

We present an exact analytic solution of a nonlinear Schrodinger field interacting with a moving potential (obstacle) at supersonic speed. We discover conditions under which the field can form a stable shape-invariant structure localized around the obstacle-a dressing effect that protects the field against excitations by the obstacle. Such an effect demonstrates the existence of frictionless motion beyond the conventionally defined critical velocity.

Journal Article↗
PubMed2000

Three clusters of ciguatera poisoning: clinical manifestations and public health implications.

Between July 1997 and August 1998 we investigated three clusters (26 cases) of ciguatera poisoning in the inner Sydney area. Tropical reef fish were implicated in each cluster. Most of those affected had musculoskeletal, neurological and gastrointestinal symptoms. The clusters raise questions about the need for rapid diagnosis and enhanced surveillance mechanisms, the regulation of fish supply, and the lack of testing facilities for ciguatera toxin.

Adolescent↗
PubMed2000

Genetic dissection of tomato bushy stunt virus p19-protein-mediated host-dependent symptom induction and systemic invasion.

The plus-sense single-stranded RNA of tomato bushy stunt virus (TBSV) encodes a 19-kDa protein, which is translated from a 3' proximal open reading frame (p19) that is entirely nested within the cell-to-cell movement gene (p22). Expression of the cytosolic p19-protein induces either a systemic lethal collapse in Nicotiana benthamiana and N. clevelandii, or necrotic local lesions on resistant N. tabacum. In spinach, the p19-protein is required at high abundance for efficient systemic invasion. This study aimed to determine whether these seemingly different host-dependent biological activities are governed by the same or separate regions on the 172 amino acid p19-protein. For this purpose, codons for charged amino acids predicted to be exposed on the surface of the polypeptide and presumably available for host-specific interactions, were targeted for mutagenesis. A total of 12 mutants were generated, which had no deficiencies in replication or cell-to-cell movement, and substitution of amino acids at the extreme N-terminal end or within the carboxyl 70 amino acids failed to cause a noticeable biological effect on plants. However, mutations dispersed between positions 43 and 85 on the N-terminal half prevented the onset of a systemic lethal necrosis on N. benthamiana and N. clevelandii. With one exception, the same mutants elicited mostly chlorotic, rather than necrotic, local lesions on N. tabacum. Mutations in the central region, which substituted Arg with Gly at positions 72 or 75-78, impaired the ability of TBSV to systemically invade spinach plants. However, substitution with Ala instead of Gly at position 72 had minimal effects on systemic spread in spinach, suggesting the possible influence of protein structure effects. The implications are that regions on the N-terminal portion of the p19-protein mediate interactions in a host-dependent manner and that a central region is required for all activities either by a direct effect of the amino acids or through maintenance of structural integrity.

Mutagenesis, Site-Directed↗
PubMed2000

Spectroscopic characterization of Co(II)-, Ni(II)-, and Cd(II)-substituted wild-type and non-native retroviral-type zinc finger peptides.

The nucleocapsid protein (NCP) from Mason-Pfizer monkey virus (MPMV) contains two evolutionary invariant Cys-X2-Cys-X4-His-X4-Cys retroviral-type zinc finger structures, where the Cys and His residues provide ligands to a tetrahedrally coordinated Zn(II) ion. The N-terminal zinc finger (F1) of NCP from MPMV contains an immediately contiguous Cys in the -1 position relative to the start of this conserved motif: Cys-Cys-X2-Cys-X4-His-X4-Cys. Metal complexes of 18-amino acid peptides which model the native zinc finger sequence, SER-Cys-X2-Cys-X4-His-X4-Cys (F1-SC), and non-native Cys-SER-X2-Cys-X4-His-X4-Cys (F1-CS) and SER-SER-X2-Cys-X4-His-X4-Cys (F1-SS) sequences have been spectroscopically characterized and compared to the native two-zinc-finger protein fragment, MPMV NCP 21-80. All Co(II)-substituted peptide complexes adopt tetrahedral ligand geometries and have S- -->Co(II) ligand-to-metal charge-transfer (LMCT) transition intensities consistent with three Co(II)-S bonds for F1-SC and F1-CS. The non-native F1-CS peptide binds Co(II) with KCo= 1.5 x 10(6) M(-1), comparable to that of the native complex, and approximately 100-fold tighter than F1-SS. Like the Co(II) derivative, the absorption spectrum of Ni(II)-substituted NCP 21-80 is most consistent with tetrahedral Ni(II) complexes with multiple thiolate donors. In contrast, Ni(II) complexes of F1-SC and F1-CS exhibit a single absorption band in the 400-550 nm region (epsilon approximately 200-300 M(-1) cm (-1), distinct in the two complexes, assignable to a degenerate d-d transition envelope characteristic of non-native square-planar coordination geometry, and an intense LMCT transition in the UV (epsilon255 approximately 14,000 M(-1) cm(-1)). Cd(II) complexes have intense absorption in the UV (lambda(max)=233nm), with absolute intensities consistent with approximately 5000 M(-1) cm(-1) per Cd(II)-S bond. 113Cd NMR spectroscopy of 113Cd MPMV NCP gives delta=649 ppm, consistent with S3N coordination. Co(II) and Cd(II) complexes of non-native F1-CS peptides are more sensitive to oxidation by O2, relative to F1-SC, suggestive of a higher lability in the non-native chelate. The implications of these findings for the evolutionary conservation of this motif are discussed.

Amino Acid Sequence↗
PubMed2000

Differential mechanisms mediating descending pain controls for antinociception induced by supraspinally administered endomorphin-1 and endomorphin-2 in the mouse.

We have previously demonstrated that both endomorphin-1 and endomorphin-2 produce their antinociception by the stimulation of mu-opioid receptors. However, the antinociception induced by endomorphin-2 contains an additional component, which is mediated by the release of dynorphin A (1-17) acting on kappa-opioid receptors. These studies were done to determine whether the antinociception induced by endomorphin-1 and endomorphin-2 given supraspinally was mediated by the activation of different descending pain control pathways in the mouse. Specific receptor antagonists or antisera against endogenous opioid peptides were injected intrathecally to block the receptors or bind the released endogenous opioid peptides, and endomorphin-1 or endomorphin-2 was then administered i.c.v. to activate the descending pain control systems to produce antinociception. The tail-flick response was used as antinociceptive test. The blockade of the alpha(2)-adrenoceptors and 5-hydroxytryptamine receptors in the spinal cord by i.t. injection of yohimbine and methysergide, respectively, inhibited the antinociception induced by i.c.v.-administered endomorphin-1 and endomorphin-2. However, the antinociception induced by endomorphin-2 was inhibited by i.t. pretreatment with delta(2)-opioid receptor antagonist naltriben or kappa-opioid receptor antagonist nor-binaltorphimine, but not by the mu-opioid receptor antagonist D-Phe-Cys-Tyr-D-Try-Orn-Thr-Pen-Thr-NH(2) or the delta(1)-opioid receptor antagonist 7-benzylidene naltrexamine. Intrathecal pretreatment with antiserum against Met-enkephalin attenuated the antinociception induced by i.c.v.-administered endomorphin-2, but not endomorphin-1. Furthermore, i.t. pretreatment with antiserum against dynorphin A (1-17) also inhibited the antinociception induced by i.c.v.-administered endomorphin-2, but not endomorphin-1. Intrathecal pretreatment with antiserum against Leu-enkephalin or beta-endorphin did not inhibit i.c.v.-administered endomorphin-1- or endomorphin-2-induced antinociception. The results indicate that, like other opioid micro-receptor agonists, morphine, and [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin, endomorphin-1 and endomorphin-2 given i.c.v. produce antinociception by activating spinipetal noradrenergic and serotonergic pathways for producing antinociception. However, the antinociception induced by endomorphin-2 given i.c.v. also contains other components, which are mediated by the release of Met-enkephalin and dynorphin A (1-17) acting on opioid delta(2)- and kappa-receptors, respectively, in the spinal cord.

Adrenergic alpha-Antagonists↗
PubMed1999

MRE-Binding transcription factor-1: weak zinc-binding finger domains 5 and 6 modulate the structure, affinity, and specificity of the metal-response element complex.

MRE-binding transcription factor-1 (MTF-1) contains six Cys(2)-His(2) zinc finger sequences, and it has been suggested that the zinc finger domain itself may function as a zinc sensor in zinc-activated expression of metallothioneins (MTs). Previous work has shown that a subset ( approximately 3-4) of the zinc fingers in MTF-zf play a structural role in folding and high-affinity metal-response element (MREd) binding, while one or more other fingers have properties consistent with a metalloregulatory role (weak zinc binding affinity in the absence of DNA). We show here that zinc fingers 5 and 6 correspond to the weak zinc-binding fingers in MTF-zf. Limited trypsinolysis of a Zn(6)-MTF-zf:MREd complex gives rise to a highly protease-resistant core fragment corresponding to amino acids 137-260 or N-terminal zinc fingers 1-4 of MTF-zf. Characterization of a collection of broken-finger (His --> Asn) and missing-finger mutants of MTF-zf reveals that deletion of zinc fingers 5 and 6 to create MTF-zf14 attenuates MREd binding affinity ( approximately 20-fold), while deletion of fingers 4-6 (MTF-zf13) results in a further 20-fold reduction of binding affinity with a nearly complete loss of specificity. Circular dichroism studies reveal that the binding of MTF-zf to the MREd induces a dramatic alteration of the structure of the MREd from a B-form to a double-helical conformation with A-like features. Formation of stoichiometric complexes with MTF-zf14, H279N (Deltazf5) MTF-zf, and MTF-zf13 induces comparatively less A-like structure. Steady-state fluorescence resonance energy transfer (FRET) spectroscopy has been used to globally define the orientation of the multifinger MTF-zf on the MREd. These experiments suggest that fingers 1-4 are oriented on the highly conserved TGCRCnC side of the MREd with fingers 5-6 bound at or near the gGCCc sequence. These findings are consistent with a model in which the N-terminal zinc fingers in MTF-zf are required for high affinity and specific binding to the consensus TGCRCnC core in a way which is subjected to structural and allosteric modulation by the weak zinc-binding C-terminal zinc fingers.

Amino Acid Sequence↗
PubMed1999

Isolation and structure of SCH 351633: a novel hepatitis C virus (HCV) NS3 protease inhibitor from the fungus Penicillium griseofulvum.

A new hepatitis C virus (HCV) protease inhibitor designated as Sch 351633 (1) was isolated from the fungus, Penicillium griseofulvum. Structure elucidation of 1 was accomplished by analysis of spectroscopic data, which determined compound 1 to be a bicyclic hemiketal lactone. Compound 1 exhibited inhibitory activity in the HCV protease assay with an IC50 value of 3.8 microg/mL.

Antiviral Agents↗
PubMed1999

Phenolic aporphine-benzylisoquinoline alkaloids from Thalictrum faberi.

From the roots of Thalictrum faberi, six new phenolic aporphine-benzylisoquinoline alkaloids, 3-hydroxy-6'-desmethyl-9-O-methylthalifaboramine (1), 3-hydroxythalifaboramine (2), 6'-desmethylthalifaboramine (3); 3,5'-dihydroxythalifaboramine (4), 5'-hydroxythalifaboramine (5) and 3-hydroxy-6'-desmethylthalifaboramine (6) were isolated. Their structures were established through the use of one- and two-dimensional NMR techniques. All of the tested alkaloids showed potent cytotoxic and antimalarial activities.

Alkaloids↗